According to the classification of cerebrovascular disorder, 3rd edition (MINDS-III, Stroke 21:637-676, 1990), National Institute of Neurological Disorders and Stroke (MINDS), cerebrovascular disorder is classified into asymptomatic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, and hypertensive encephalopathy. The type of cerebral apoplexy includes cerebral hemorrhage, subarachnoid hemorrhage, cranial hemorrhage accompanying a malformation in cerebral arteries and veins, and cerebral infarction, and there are many diseases causing each of them. In the past, hypertensive cerebral hemorrhage was a major disease, but by finding and managing hypertension at an early stage and westernization of nutrition intake, the rate of occurrence thereof and the death rate are gradually reduced, while the absolute number of old men with cerebral infarction and the ratio thereof are increasing due to spread of various kinds of image diagnosis techniques. Cerebral infarction is classified into atherothrombotic cerebral infarction, lacuna infarction, and cardiogenic cerebral infarction, among which lacuna infarction is decreasing with the progress of treatment of hypertension. On the other hand, the ratio of atherothrombotic cerebral infarction and cardiogenic cerebral infarction is increasing due to westernization of nutrition intake.
In Japan, these cerebrovascular disorders are at the second place of causes of death or at the top of causative diseases for bedridden old men at present, and thus countermeasures not only for prevention of occurrence of cerebrovascular disorder but also for prevention of recurrence thereof and progress of troubles following cerebrovascular disorder become important problems.
Medical treatment of cerebrovascular disorder is divided by a stage of diseases (acute stage, subacute stage, chronic stage, asymptomatic stage), a type of diseases (hemorrhagic, ischemic, etc.) and severity of diseases (presence or absence of hernia).
Treatment of cerebral apoplexy at an acute stage and a subacute stage includes systemic management including blood pressure, as well as inhibition of cerebral edema, measures against complications (hemorrhage in digestive tracts, infections in respiratory organs, convulsions, unrest, etc.), brain-protecting therapy (treatment by a brain-protecting drug, cryotherapy, etc.) and antithrombotic therapy depending on a particular type of diseases (treatment with thorombolytics, antiplatelets, anticoagulants, etc.), etc. For cerebral apoplexy at an acute stage, it is necessary to take a measure against cerebral edema in every type of diseases. Cerebral edema occurring at an acute stage of cerebrovascular disorder is a phenomenon in which the blood-brain barrier is disturbed by damage to brain, and fluid components in brain tissues are increased to increase the volume of brain, against which chemotherapy is generally conducted by intermittent administration of steroids or by intravenous injection of a hypertonic solution such as mannitol or glycerin. At an acute stage of cerebral apoplexy, in addition to a reactive increase in blood pressure, there are various changes in cerebral circulation kinetics, that is, a decrease in a cerebral blood flow rate not only in foci but also in a surrounding penambra region and in a part distant from foci in the brain, disorder in the ability for automatic regulation of cerebral blood flow, a reduction in CO2 reactivity in cerebral vessels, etc. Accordingly, there is danger that a careless and significant reduction in blood pressure permits cerebral blood flow to be reduced depending on blood pressure and a penambra region can be exposed to irreversible danger. Then, use of an antihypertensive is restricted in principle, unless complications with severe hypertension and organ disorders attributable to hypertension such as heart failure are present. In the case of cerebral hemorrhage, however, there is danger of increasing hematocele, and thus about 20% reduction in blood pressure is often recommended, and in the case of subarachnoid hemorrhage, an increase in blood pressure causes re-bleeding and significantly influences the prognosis of life, and thus a durable depression in blood pressure is required.
Major medical treatment at a chronic stage involves a measure against troubles following cerebrovascular disorder and a measure for preventing recurrence thereof, depending on a particular type of diseases. The troubles following cerebrovascular disorder are classified roughly into nerve symptoms, mind symptoms, subjective symptoms (non-localizing subjective symptoms, localizing subjective symptoms, etc.), and obstacles in activities of daily living (ADL). In chemotherapy for these troubles following cerebrovascular disorder, nerve symptoms are limited to symptomatic therapy by an antispasmodic, etc. Chemotherapy is mainly directed to amelioration of nerve symptoms and subjective symptoms and uses agents for ameliorating cerebral circulation, agents for ameliorating cerebral metabolism (neurotransmission ameliorating agents, cerebral metabolism-activating agents, etc.) and psychotropics (anti-schizophrenia, anti-anxiety, antidepressant, etc.). Major treatment of obstacles in ADL involves rehabilitation, and chemotherapy is used as an aid to promote rehabilitation. Measures for preventing recurrence of cerebrovascular disorder include not only treatment (indirect measures) of diseases serving as factors causing hypertension, diabetes, hyperlipemia, etc., but also chemotherapy using antiplatelets, anti-coagulants, etc. depending on a particular type of diseases. However, there is no report suggesting that a compound having an AII antagonistic activity can be used in a direct measure for preventing recurrence of cerebrovascular disorder or for ameliorating troubles following cerebrovascular disorder and inhibiting progress thereof.
While treatment at an acute stage is the most important for treatment of cerebrovascular disorder from the viewpoint of medical economy, prevention of recurrence thereof and its progress are also major problems. However, only an antiplatelet is used for preventing recurrence of cerebrovascular disorder, and its usefulness is low.
The most dangerous factor for cerebrovascular disorder is hypertension, while the dangerous factors for cerebral infarction include an abnormality of sugar resistance and an abnormality in electrocardiogram, and the dangerous factors for cerebral hemorrhage include an abnormality in electrocardiogram, an abnormality in eye ground and drinking, and the like. As the dangerous factors for recurrence of cerebrovascular disorder, hypertension, cardiac disorders, TIA, diabetes, etc. are pointed out, and it can be considered that antihypertensive therapy is applied not only to prevention of occurrence of cerebrovascular disorder (primary prevention) but also to prevention of recurrence thereof (secondary prevention). However, usually hypertension accompanying cerebral apoplexy causes complications with diabetes, hyperlipemia and obesity, and accompanies high rates of vascular lesions in hearts, kidneys and peripheral arteries, and in such conditions, a presently existing antihypertensive therapy does not necessarily prevent the recurrence of cerebral apoplexy. This is because, in cerebral infarction after the onset, it is considered that cerebral arteriosclerotic lesions also proceed, and conventional antihypertensives cannot be expected to ameliorate such vascular lesions. Further, atherothrombotic cerebral infarction accompanying constriction and occlusion of a major stem artery occurs due to kinetics of the blood flow mechanism, so hypotension is considered to cause cerebral ischemia. In particular, the ability for automatic regulation of cerebral circulation has failed at an acute stage of cerebral apoplexy, and therefore rapid depression in blood pressure could conversely cause a reduction in cerebral blood flow to permit progress of cerebral ischemia. Further, at a chronic stage of 1 month or more after the onset of disease conditions, wherein antihypertensive therapy is usually initiated, the upper and lower limits of automatic regulation ability are deviated rightward (toward higher blood pressure level) in old men or patients with hypertension and cerebrovascular disorder, so even a slight depression in blood pressure causes a reduction in cerebral blood flow, to cause recurrence of cerebral ischemia. Further, patients with hypertension and cerebrovascular disorder often exhibit a non-dipper where blood pressure at night is increased even by administration of an antihypertensive, or an extra-dipper where blood pressure at night is too lowered, and hypertension is caused in early morning, and this change in blood pressure serves as a cause for inducing recurrence of cerebral apoplexy. Accordingly, there is demand for a drug having an anti-arteriosclerosis action, not lowering blood flow, improving the ability for automatic regulation of cerebral blood flow, and showing a stable and durable antihypertensive action.
At present, a long-lasting Ca antagonist or an angiotensin converting enzyme (ACE) inhibitor is used as an antihypertensive as a first choice in consideration of its action on cerebral circulation and cerebral vessels, and other drugs used include vasodilative β- or α1-blockers. However, these drugs have problems with significant depression in blood pressure, duration of their action, and their side effects, and at present there is no ideal drug. Among them, due to a mechanism which is presumed to be attributable to a reduction in angiotensin II (AII) production in cerebral endarterium, the ACE inhibitor can particularly deviate the ability for automatic regulation of cerebral circulation leftward (toward lower blood pressure level), thus preventing or reducing cerebral ischemia developed by kinetics of the blood flow mechanism, and in this respect, the ACE inhibitor is a useful drug. However, the ACE inhibitor has the activity of not only inhibiting AII production but also decomposing inflammatory mediators such as bradykinin and substance P, and because of coughs and vascular edemas resulting therefrom, administration of the drug should inevitably be terminated in many cases. Further, an enlargement of edemas and cellular disorder may be induced due to enhancement of the inflammatory action, and particularly pathema at an acute stage (including ultra-acute stage to subacute stage) significantly influencing prognosis could be significantly worsened. Further, at present, there are little drugs (excellent in T/P ratio) showing stable depression in blood pressure through 24 hours, and in patients exhibiting a non-dipper having recurrence of cerebrovascular disorder at high rate or patients exhibiting hypertension in early morning, sufficiently stable depression in blood pressure cannot be achieved.
On the other hand, it is described that a compound having an antagonism to AII is known as an agent for treating diseases in circulatory organs, such as hypertension, cardiac diseases (cardiac hypertrophy, heart failure, myocardial infarction, etc.), cerebral apoplexy, nephritis, etc. (JP-A 4-364171, etc.), and it is demonstrated that AII having a strong vasoconstrictor action is prevented from acting on AII receptors by this compound to exhibit a durable action of depressing blood pressure.
Further, it is reported that Candesartan, i.e. an active metabolite of Candesartan cilexetil can deviate the lower limit of automatic regulation leftward (toward lower blood pressure level) (Vraamark T et al., J Hypertens 13:755-761, 1995), but there is no report suggesting that a compound having AII antagonistic activity is useful as an agent for preventing recurrence of cerebrovascular disorder or as an agent for ameliorating troubles following cerebrovascular disorder and inhibiting progress thereof.